肝細(xì)胞癌分子進(jìn)行靶向治療研究進(jìn)展

1、肝細(xì)胞癌分子靶向治療的研究進(jìn)展南京八一醫(yī)院全軍腫瘤中心秦叔逵,HCC發(fā)生的分子機(jī)制,,3,,HCC的靶向治療藥物,概述,結(jié)語,,4,概述,原發(fā)性肝癌是臨床上最常見的惡性腫瘤之一，其中，90%為肝細(xì)胞癌(HCC)，其他為膽管細(xì)胞癌(ICC)和混合性肝癌等；全球的HCC發(fā)病率呈上升趨勢，年發(fā)病約74.8萬人，居于惡性腫瘤發(fā)病率的第5位，中位年齡50～60歲，男：女=4：1；HCC已成為癌癥導(dǎo)致死亡的主要原因之一，全球每年有近6

2、9.6萬人死于該病。,概述,主要高發(fā)區(qū)為中國、東南亞、非洲東南部和地中海沿岸國家；由于HCC的臨床征象通常出現(xiàn)較晚，發(fā)現(xiàn)時往往已為疾病的中晚期，因此，HCC的癥狀曾被認(rèn)為是臨終階段表現(xiàn)，多年來，并未引起醫(yī)學(xué)界足夠的重視；近年來，HCC的治療有了重要突破，主要是分子靶向治療的巨大進(jìn)步，石破天驚，引起廣泛的關(guān)注，成為治療和研究的熱點。,HCC:全球第6位常見腫瘤,1. Garcia M, et al. American Cancer S

3、ociety, 2007. www.cancer.org. Accessed March 20, 2008. 2. Pons-Renedo F, et al. Med Gen Med. 2003;5:11.,HCC is the third most common cause of cancer-related death Incidence is rising in US and Europe,CA: Cancer J Clin 2

4、011.,全球癌癥新發(fā)和死亡病例（2008）,,,,,近20年來，不管是在發(fā)達(dá)國家（如美國）還 是在發(fā)展中國家或貧窮落后國家，原發(fā)性肝癌的發(fā)病率和病死率均呈上升趨勢。 在中國，盡管采取了“改水、防霉、防肝炎”等一系列預(yù)防措施，但多年來肝癌的發(fā)病率和病死率仍未見明顯回落。,Thomas MB, et al. Hepatocellular Carcinoma: The Needs for Progress.J Clin Oncol,200

5、5,23: 2892-9.,HCC:流行病學(xué),晚期HCC:基本概念,由于肝癌的侵襲性和生長迅速，大多數(shù)肝癌患者（特別是亞洲患者）在確診時已達(dá)局部晚期和/或遠(yuǎn)處轉(zhuǎn)移，往往不適合手術(shù)切除、TACE或其他局部治療，因此歸于晚期HCC, 包括BCLC分期為C期和D期的患者。晚期HCC患者預(yù)后很差，如果僅僅進(jìn)行對癥支持治療，在西方國家其平均生存期在6-9個月，在東亞國家僅3-4個月。,晚期 HCC:基本概念,一般認(rèn)為, HCC的高度異質(zhì)性是東西

6、方晚期HCC患者生存率存在差異的主要原因。亞洲和西方國家的HCC在病因?qū)W、分期、生物學(xué)惡性行為、診治（治療觀念和臨床實踐指南）以及預(yù)后等方面都存在明顯差異;因此,有人認(rèn)為可以看作是”兩種病”。,HCC治療：面臨的挑戰(zhàn),一個患者同時并存兩類疾病，病情復(fù)雜,互相影響:高度侵襲性的肝臟原發(fā)性腫瘤:起病隱襲，生長迅速，倍增時間3個月；極易侵犯脈管和轉(zhuǎn)移播散。約80%的患者合并有肝炎和肝硬化:肝炎活動或纖維化，肝功能受損，往往失代償；

7、肝硬化結(jié)節(jié)，腫瘤常是多中心發(fā)生。,HCC的危險因素: 地域差異,20%,50-70%,70%,70%,10-20%,10-20%,10-20%,≤10%,丙肝,亞洲/非洲*,,,,,*日本除外,,,,,酒精,其他,乙肝,日本,歐洲/北美,所有地區(qū),Llovet JM, et al. Lancet 2003;362:1907–17,流行病學(xué)：亞太地區(qū)與美國,亞洲主要為乙型肝炎：每年5–7%病例將患HCC大多數(shù)亞洲國家丙型肝炎-日

8、本和印尼排名第55年總存活率<10%年齡校正后的年發(fā)病率在27.6-36.6例/10萬人/年男女比例為4:1,美國主要為丙型肝炎，每年有2–8%病例將患HCC排名第4（亞裔）―第8（拉美裔）5年總存活率為8%年齡校正后的年發(fā)病率為3.4例/10萬人非洲裔和亞裔美國人的發(fā)病率為白人的1.7-4倍。所有人種中，均以男性為主,1. Teo EK, et al. Dig Dis 2001;19:263-268; 2.

9、 Ahmed F, et al. Prev Chronic Dis CDC 2008;5(3); 3. NCCN Hepatobiliary cancers practice guideline 2009;2.,HCC發(fā)生的分子機(jī)制,,3,,HCC的靶向治療藥物,概述,結(jié)語,,4,肝細(xì)胞癌發(fā)生的分子基礎(chǔ),HCC 的分子發(fā)病機(jī)制極其復(fù)雜慢性HBV/HCV 感染或環(huán)境毒素,引發(fā)肝硬化并誘導(dǎo)肝細(xì)胞基因水平的病變信號傳導(dǎo)途徑異常導(dǎo)致細(xì)胞異常

10、增生及存活異常的生長因子激活 (TGF-β, EGFR)細(xì)胞分裂信號途徑的持續(xù)活化 (Raf/MEK/ERK, PI3K/AKT, Wnt ) 抗細(xì)胞凋亡信號途徑失調(diào) (p53, PTEN)新生血管異常增生（如VEGF途徑）, 促進(jìn)腫瘤生長及進(jìn)展,,肝細(xì)胞癌發(fā)生的分子機(jī)制,Normal Liver,Liver Cirrhosis,Genetic Alterations,Epigenetic Alterations,HCC,Dy

11、splastic Nodules,Lab Invest 2002; 852:547-554,肝細(xì)胞癌發(fā)生的分子機(jī)制,Oncogene , 2010,29, 4989–5005,肝細(xì)胞癌發(fā)生的分子機(jī)制,,Nucleus,,,,PI3K,AKT,STAT,,,mTOR,,,,Transcription Factors,,,,,Cell proliferation,Angiogenesis,Metastases,,Survival/?Apo

12、ptosis,,VEGFR,PDGFR,EGFR,Bevacizumab,VEGF,Cetuximab,IMC-1121b,血管生成在腫瘤的發(fā)生發(fā)展中起重要作用,Cancer Letters 2006;242:151–167,分子靶向治療已成為腫瘤治療的重要手段,血管生成在HCC生長轉(zhuǎn)移中起重要作用,HCC是典型的富血管腫瘤HCC的生長和代謝,需要持續(xù)的血管生成 HCC血管新生與其生長、浸潤、轉(zhuǎn)移、分期及預(yù)后有著密切聯(lián)系,HCC與促

13、血管新生因子,HCC分泌大量的促血管新生因子，包括：血管內(nèi)皮生長因子(VEGF)血小板衍生性生長因子( PDGF)胎盤生長因子轉(zhuǎn)化生長因子α和β ( TGFα、β)堿性成纖維細(xì)胞生長因子( bFGF)表皮生長因子( EGF)肝細(xì)胞生長因子( HGF),VEGF在腫瘤生長轉(zhuǎn)移過程中起重要作用,Nat Rev Cancer 2008;8(8):579-91.,HCC發(fā)生發(fā)展過程涉及多種信號通路,Nat. Rev. Gastro

14、enterol. Hepatol 2009,6:423–432,Raf/MEK/ERK信號通路與HCC密切相關(guān),Expert Opin Emerg Drugs ,2006;11:469-87,與肝癌細(xì)胞生長和轉(zhuǎn)移復(fù)發(fā)相關(guān)的分子通路,主要有4條：Ras/Raf/Mek/Erk、PI3k/Akt/mTOR、Wnt/β-catenin和核因子-κB （NFκB）;Ras/Raf/Mek/Erk通路調(diào)節(jié)細(xì)胞增殖、分化、血管生成和存活;在HC

15、C中過度活化,可能通過以下因素:癌基因Ras突變生長因子和其受體的異常過度表達(dá)導(dǎo)致Raf組成性激活肝炎病毒蛋白,HCC發(fā)生的分子機(jī)制,,3,,HCC的靶向治療藥物,概述,結(jié)語,,4,分子靶向藥物—激光制導(dǎo)炸彈,主要是針對腫瘤發(fā)生、發(fā)展過程中的關(guān)鍵大分子，即參與腫瘤發(fā)生、發(fā)展過程中的細(xì)胞信號傳導(dǎo)和其他生物學(xué)途徑的重要靶點,或是通過強(qiáng)力阻止腫瘤血管生成，從而抑制腫瘤細(xì)胞的生長、增殖和轉(zhuǎn)移播散，發(fā)揮特異性抗腫瘤作用。,在研的HCC靶向

16、治療藥物作用的信號通路,Sunitinib Brivanib,靶點和藥物EGFR: TKI: Erlotinib, LapatinibGefitinib Ab: CetuximabVEGF TKI: Sorafenib Sunitinib Brivanib Ab: BevacizumabRAF TKI: SorafenibmTOR Rapamyci

17、n，CCI-779蛋白酶體抑制劑 Bortezomib,生長因子受體信號通路,分子靶向藥物—激光制導(dǎo)炸彈,主要是針對腫瘤發(fā)生、發(fā)展過程中的關(guān)鍵大分子，即參與腫瘤發(fā)生、發(fā)展過程中的細(xì)胞信號傳導(dǎo)和其他生物學(xué)途徑的重要靶點,或是通過強(qiáng)力阻止腫瘤血管生成，從而抑制腫瘤細(xì)胞的生長、增殖和轉(zhuǎn)移播散，發(fā)揮特異性抗腫瘤作用。,在研的HCC靶向治療藥物的作用靶點,Clin Cancer Res 2010; 16(2); 390–7.,已發(fā)表的肝癌靶

18、向治療的臨床研究,Clin Cancer Res ,2010; 16(2); 390–7.,1. 抗血管生成的靶向藥物2. 靶向EGFR信號通路的藥物3. 靶向PI3K/AKT/mTOR信號通路的藥物4. 其他新型分子靶向藥物,√,HCC的靶向治療藥物,研發(fā)中的VEGFR靶向治療藥物 for HCC,,Verweij J, DeJorge M. J Clin Oncol. 2007;25(17):2340-2343.; Nat

19、ional Cancer Institute Clinicial Trials Registry. Avaialbe at: http://www.clinicaltrials.gov. Accessed May 20, 2008.,(1) 索拉非尼,索拉非尼：同時抗腫瘤血管生成和細(xì)胞增殖,Clin Cancer Res 2004;64:7099-7109.,索拉非尼—全球首個FDA批準(zhǔn)的HCC靶向治療藥物,索拉非尼治療HCC的基

20、礎(chǔ)和I期研究,索拉非尼在HCC臨床前研究1：抗HCC細(xì)胞增殖、誘導(dǎo)細(xì)胞凋亡和抗血管生成抑制小鼠異體移植模型中HCC腫瘤的生長 索拉非尼的 I 期臨床研究2：不同種族間,無顯著藥代動力學(xué)差異Child?Pugh A級和B級間無顯著藥代動力學(xué)差異耐受良好，具有明確的臨床獲益,1. Cancer Res 2006;66:11851-118582. Cancer Sci. 2007:1-7,索拉非尼治療晚期HCC 的Ⅱ期研究,13

21、7/147例,抗腫瘤活性明顯：獲得8%(11/137)的 PR或MR, 34%(46/137)的SD≥16 周 獨立評價的mTTP為5.5 個月獨立評價的mOS為9.2 個月患者的耐受性良好:Child–Pugh A 和 B 級患者間無臨床藥代動力學(xué)差異索拉非尼在兩個Child-Pugh 亞組中均耐受良好,J Clin Oncol 2006;24:4293–300,索拉非尼治療晚期HCC Ⅲ期研究： 顯著改善總生存,1.

22、N Engl J Med 2008;359:378-90.2. Lancet Oncol 2009; 10: 25–34,索拉非尼：開啟了HCC靶向治療新時代,迄今為止，在HCC領(lǐng)域開展的隨機(jī)試驗已經(jīng)超過了100項;索拉非尼是第一個被證實可以改善晚期HCC病人mOS的系統(tǒng)性治療藥物;目前，索拉非尼在全球 超過60個國家/地區(qū)被批準(zhǔn)用于晚期HCC/無法手術(shù)切除HCC的治療；現(xiàn)在, 多項索拉非尼治療HCC的臨床試驗正在積極開展，覆蓋

23、了HCC的的不同階段。,已完成或正在開展的索拉非尼治療HCC的大型研究,GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) second interim analysis in >1500 patients: clinical find

24、ings in patients with liver dysfunction,Jorge A. Marrero, M.D., M.S.Comprehensive Cancer Center,University of Michigan, Ann Arbor, MI, United States,R. Lencioni, M. Kudo, S. L. Ye, K. Nakajima, F. Cihon, A. Venook,背景介

25、紹,Sorafenib is the only systemic therapy indicatedto treat HCC1In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC2-3 Pivotal studies generally included patient

26、s with preserved liver function Investigation of sorafenib in wider patient groups is needed4 GIDEON is the largest prospective study in uHCC ever conducted In total, 3322 patients have been enrolled from 39 countries

27、,uHCC, unresectable hepatocellular carcinoma; OS, overall survival;GIDEON, Global Investigation of therapeutic DEcisions in hepatocellularcarcinoma and Of its treatment with sorafeNib,1. NCCN Guidelines, 2009;2. Llove

28、t et al, 2008; 3. Cheng et al, 2009;4. Lencioni et al, 2010,GIDEON 研究設(shè)計和目標(biāo),GIDEON is a non-interventional studyPrimary objective: to evaluate safety of sorafenib in patients with uHCC who are candidates for systemic th

29、erapy and for whom the decision to treat with sorafenib was made in clinical practice Secondary objectives: efficacy, duration of therapy; methods of patient evaluation, diagnosis and follow-up; co-morbidities and pract

30、ice patternsGIDEON will also provide information in patient subgroups where data are currently limitedIncluding patients with Child-Pugh B status who were generally excluded from sorafenib Phase III trials in uHCC,GIDE

31、ON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib; uHCC, unresectable hepatocellular carcinoma,GIDEON 研究: 療效評價,GIDEON has a non-randomized, uncontrolled non

32、-interventional study designEfficacy is a secondary, not a primary, objectiveAll planned efficacy evaluations are descriptive in nature and subgroups are pre-specifiedTumor assessment by RECIST is not mandated in GIDE

33、ONAssessment and analysis of time to radiological PD Time is days from start of treatment to date of first documented PD Only radiologically documented PD of the tumor is considered as PD TTP for patients without doc

34、umented PD at time of analysis is censored at last date of tumor evaluation,GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib;PD, progression of diseas

35、e; RECIST, Response Evaluation Criteria In Solid Tumors; TTP, time-to-progression,GIDEON 研究:第二次second 中期分析,GIDEON second interim analysis:Per protocol the second interim analysis was planned when ~1500 treated patients

36、 were followed for ≥4 months1571 patients in the safety populationIncludes patients who received ≥1 dose of sorafenib and had ≥1 follow-up assessment after start of treatment1612 patients in the ITT populationITT pop

37、ulation used for analysis of OS and TTPIncludes patients who received ≥1 dose of sorafenib >2 days before study entry; excludes patients previously treated with sorafenibAll statistical analyses performed were descr

38、iptive in nature,Lencioni et al, 2010,GIDEON, Global Investigation of therapeutic Decisionsin hepatocellular carcinoma and Of its treatment with sorafeNib; ITT, intent to treat; OS, overall survival; TTP, time-to-progre

39、ssion,根據(jù)治療開始時Child-Pugh狀態(tài)選擇的病例基線特征(1),aChild-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulatedECOG PS, Eastern Cooperative Oncology Group performance status,根據(jù)治療開始時Child-Pugh狀態(tài)選擇的病例基

40、線特征(2),aChild-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulatedBCLC, Barcelona Clinic Liver Cancer; TNM, tumor node metastases,初始時Child-Pugh狀態(tài)與 sorafenib 劑量,aInitial dosing data missi

41、ng for 8 patients; Child-Pugh status unknown for 5 patients,初始時Child-Pugh狀態(tài)與Sorafenib 劑量和日平均劑量,aData at study entry; bDosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; cAssessed in the 79% of

42、 patients for whom dosing data were available,Child-Pugh狀態(tài)與Sorafenib 劑量中斷和調(diào)整,aData at study entrybDosing data missing for 8 patients; Child-Pugh status unknown for 5 patients,Child-Pugh狀態(tài)與Sorafenib 治療療程,aData at study

43、 entry,Child-Pugh狀態(tài)與總體安全性數(shù)據(jù),aData at study entry; bChild-Pugh status missing or not evaluable for 56 patients; cAn SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; lif

44、e-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; medically important event; dAny AE; eTreatment-emergent de

45、aths occurring up to 30 days after last sorafenib doseAEs, adverse events; SAEs, serious adverse events,Child-Pugh B 分值與總體安全性數(shù)據(jù),aData at study entry; bPatients with Child-Pugh status available; cAn SAE is defined as an

46、y AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenita

47、l anomaly / birth defect; medically important event; dAny AE; eTreatment-emergent deaths occurring up to 30 days after last sorafenib doseAEs, adverse events; SAEs, serious adverse events,Child-Pugh狀態(tài)與藥物相關(guān)性不良事件a,b,aInc

48、idence ≥5% in any group and any grade; bAt start of therapyHFSR, hand-foot skin reaction; NOS, not otherwise specified,Sorafenib治療過程中或停止治療30天內(nèi)死亡原因,aIncidence >2% in total group; bPatients may be included in more tha

49、n one cause of death category; bBy Child-Pugh status at study entry; dChild-Pugh status missing for 1 patient; eData missing for 7 Child-Pugh A and 7 Child-Pugh B patientsHCC, hepatocellular carcinoma; MOF, multi-organ

50、system failure,Child-Pugh狀態(tài)與初步的OS,Child Pugh A (<7) (n=984), median (95% CI) 312 (284, 341) days10.3 months,Child Pugh B (7-9) (n=376), median (95% CI) 147 (126, 189) days4.8 months,Child Pugh C (>9) (n=36), medi

51、an (95% CI) 62 (46, 94) days2.0 months,,,,,,,,,,,,,,,,,,,600,500,400,300,200,100,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,,,Time since start of treatment (days),Survival distribution function,,,,,,a207 patients not eva

52、luableCI, confidence interval,Child-Pugh狀態(tài)與初步的TTP,Child Pugh A (<7) (n=984), median (95% CI) 129 (119, 146) days4.2 months,Child Pugh B (7-9) (n=376), median (95% CI) 109 (93, 140) days3.6 months,Child Pugh C (>

53、9) (n=36), median (95% CI) 64 (28, 110) days2.1 months,,,,,,,,,,,,,,,,,,,500,400,300,200,100,0,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,,,Time since start of treatment (days),TTP distribution function,,,,aTTP was doc

54、umented radiological disease progression; RECIST v 1.0 used for tumor evaluation; b207 patients not evaluableTTP, time-to-progression; RECIST, Response Evaluation Criteria In Solid Tumors,結(jié)論 (1),Based on the second inte

55、rim analysis, there is no evidence suggesting that treating physicians use a different dosing strategy for Child-Pugh B patients compared with Child-Pugh A patientsDuration of sorafenib therapy was shorter in Child-Pugh

56、 B patients than in Child-Pugh A patientsCompared with Child-Pugh A patients, Child-Pugh B patients did not have a higher incidence of drug-related AEs, but had a higher incidence of liver-associated AEsIn patients wit

57、h moderate liver dysfunction, no unexpected AEs were observed,AEs, adverse events; SAEs, serious adverse events,結(jié)論 (2),The vast majority of deaths were due to HCC or underlying liver disordersThe differences in patient

58、outcomes across Child-Pugh groups likely reflect differences in prognosis Consistent with previously reported studies, these preliminary data indicate that Child-Pugh status appears to be a useful prognostic factor for

59、overall survivalThe GIDEON study is ongoing, and the safety, tolerability, and efficacy of sorafenib in HCC patients will continue to be evaluated,HCC, hepatocellular carcinoma; GIDEON, Global Investigation of therapeut

60、ic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib,阿霉素±索拉非尼治療HCC的II期研究——研究結(jié)果已經(jīng)發(fā)表,,,阿霉素±索拉非尼治療HCC的II期研究,Abou-Alfa GK, et al. EJC Suppl. 2007;5(4):259. ASCO-GI 2008.1報告.,月,,,,,,,,,,,,,

61、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,無進(jìn)展率,,,,,,,,,,,,,

62、1.00,0,0.75,0.50,0.25,0,15.5,5.0,7.5,10.0,12.5,2.5,HR： 0.60 P = 0.076,,阿霉素 + 索拉非尼 mTTP： 8.6個月,阿霉素 + 安慰劑 mTTP： 4.8個月,,,,,,截尾數(shù)據(jù),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

63、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,生存率,1.00,0,0.75,0.50,0.25,0,20.0,5.0,7.5,10.0,12.5,15.0,17.5,2.5,HR= 0.45 P = 0.0049,月,阿霉素 + 索拉非尼 mOS： 13.7個月,阿霉

64、素 + 安慰劑 mOS： 6.5個月,,,ADM + Sor mTTP： 8.6個月ADM + 安慰劑 mTTP：4.8個月,ADM + Sor mOS： 13.7個月ADM + 安慰劑 mOS：6.5個月,,,,截尾數(shù)據(jù),ADM用量: 60 mg/m2,2 PR,62%,1 PR,29%,阿霉素±索拉非尼治療HCC的II期研究,阿霉素±索拉非尼治療HCC的III期研究,,,索拉非尼聯(lián)合小劑量替加氟∕尿

65、嘧啶治療晚期HCC的II期研究,結(jié)論：給予小劑量的替加氟∕尿嘧啶（125 mg/m2 BID）聯(lián)合索拉非尼治療晚期肝癌是安全有效的，可以有效地提高索拉非尼的療效,Hsu CH, et al. Journal of Hepatology 2010;53:126-131,納入53例晚期HCC患者（72%為HBSAg陽性），單臂研究,100,80,60,40,20,0,0,5,10,15,20,25,PFS,%,,mPFS 3.7 個月（

66、95%CI:1.9~5.5）,時間（月）,100,80,60,40,20,0,0,5,10,15,20,25,OS,%,mOS 7.4 個月（95%CI:3.2~11.6）,,3.索拉菲尼聯(lián)合方案,Yau T, et al. 34th ESMO Multidisciplinary Congress (European Journal of Cancer Supplements, Berlin) 2009. p. 1-24,,香港瑪麗

67、醫(yī)院,51例亞洲晚期HCC患者,SECOX,84%的患者為HBV攜帶者，98%肝功能為 Child A,索拉非尼 400 mg bid d1-14+OXA 85 mg/m2 d1， Xeloda 1700 mg/m2 d1-7,RR 16%, mPFS 7.3 m，mOS 10.8m,,,,索拉非尼聯(lián)合卡培他濱、奧沙利鉑（SECOX) 治療晚期HCC的II期研究,索拉非尼聯(lián)合卡培他濱、奧沙利鉑（

68、SECOX)治療晚期HCC的II期研究,http://clinicaltrials.gov/ct2/results?term=SECOX+AND+HCC,納入51例晚期HCC患者（84%為HBSAg陽性），單臂研究,,結(jié)果：SECOX方案可以延長患者的mPFS和mOS,100,80,60,40,20,0,0,3,6,9,12,21,PFS,%,mPFS 7.1 個月（95%CI: 1.6~19.9）,時間（月）,,100,80,60